Familial clustering of early-onset prostate cancer best fits a model of autosomal dominant inheritance of a rare high risk allele, predisposing 5% of all prostate cancer occurrence. Prostate cancer is inherited in a Mendelian fashion in these families, providing an opportunity to apply linkage analysis to this complex disease. We have developed high-throughput genotyping methods to enable genotyping of 80 affected families at a 10 cM density, with an estimated error rate of 0.3% and failure rate of 2%. Panels of fluorescently-labelled dinucleotide repeat markers are co-electrophoresed in a multiplex process on automated DNA sequencers. Alleles are identified and Mendelian inheritance check is performed using GENOTYPER software. Both model-free and traditional parametric linkage analysis are being used in the study. With identification of linkage, we will initiate physical mapping of the region(s). We have also initiated the collaboration of affected sib pairs with prostrate cancer in Finland, in order to supplement the large number of pedigrees being studied through our collaboration with Johns Hopkins University.